Doi:10.1016/j.eururo.2006.03.018

e u r o p e a n u r o l o g y 5 0 ( 2 0 0 6 ) 2 1 5 – 2 1 7
a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m
j o u r n a l h o m e p a g e : w w w . e u r o p e a n u r o l o g y . c o m
Editorial – referring to the article published on pp. 351–359 of this issue
Treatment of Erectile Dysfunction with Chronic Dosingof Tadalafil
The medical management of erectile dysfunction
significant cardiac risk factors, suggesting that ED
(ED) was re-defined following the recognition that
may be the first clinical manifestation of cardiovas-
the signalling system of nitric oxide–cyclic guano-
sine-3050-monophosphate (NO-cGMP) was pivotal in
It is speculative—but likely—that chronic PDE-5
the production of the arterial dilation and venous
inhibitor treatment will improve endothelial func-
occlusion necessary to attain and sustain an erec-
tion and cardiovascular health in general. Sildenafil
tion. In parallel with this new understanding of the
has been reported to improve endothelium-depen-
mechanism of penile erection, several phospho-
dent, flow-mediated vasodilatation in smokers and
diesterase type 5 inhibitor drugs (PDE-5s), which
in patients with diabetes mellitus or chronic heart
inhibit the breakdown of cGMP producing vasodila-
failure . Chronic therapy with tadalafil has been
tation and improve endothelial cell function, have
reported to improve endothelial function and
been developed and demonstrated to be effective in
erectile function in patients with and without
treating erectile dysfunction. However, the para-
cardiovascular risk factors Chronic treatment
digm for the medical treatment of erectile dysfunc-
with a PDE-5 inhibitor may produce functional
tion remains unchanged in that it includes on-
tissue modifications involving upregulation of
demand dosing of medication. Whilst on-demand
either muscarinic receptors or the transduction
dosing reflects the intermittent nature of sexual
mechanisms leading to the activation of endothelial
intercourse, currently is more cost-effective than
nitric oxide synthase . In addition to their role in
chronic dosing and may be reasonable for many
the treatment of erectile dysfunction and pulmon-
men with erectile dysfunction, it ignores the
ary hypertension, recent reports suggest a potential
potential corporal, cardiovascular and relationship
role exists for the use of daily PDE-5 inhibitors in the
benefits of chronic PDE-5 inhibitor dosing.
treatment of other forms of cardiovascular disease
Penile vascular disease is the most common
such as hypertension. Although administration of
cause of erectile dysfunction, accounting for up to
PDE-5 inhibitors to healthy normotensive subjects
80% of cases. Abnormalities of the NO-cGMP–
results in only modest lowering of systolic and
signalling system attributable to endothelial dys-
diastolic arterial pressures, a greater decrease may
function are present in atherosclerosis and play an
occur in subjects with hypertension and increased
important role in the pathophysiology of erectile
systemic vasoconstriction related to raised levels of
dysfunction . Endothelial dysfunction may be
angiotensin II, especially if angiotensin II antago-
present in patients with ED even in the absence of
DOI of original article: 10.1016/j.eururo.2006.02.052* Tel. +61 2 94373906; Fax: +61 2 99065900.E-mail address:
0302-2838/$ – see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.
e u r o p e a n u r o l o g y 5 0 ( 2 0 0 6 ) 2 1 5 – 2 1 7
The prolonged half-life of tadalafil (17.5 hours)
pared with on-demand tadalafil ( p < 0.05). At the
and the resultant prolonged 36-hour period of
completion of the study, 72% preferred daily
responsiveness constitute an ideal pharmacokinetic
tadalafil. The 14 European country, multicenter,
profile for chronic dosing, compared with short half-
crossover, open-label SURE study examined subject
life PDE-5 inhibitor drugs. Over a dose range of 2.5 to
preference for tadalafil taken on-demand or 3 times/
20 mg, tadalafil systemic exposure increases pro-
week The authors reported that both regimens
portionally with the dose in healthy subjects.
were efficacious and well tolerated, and that 42.2%
Steady-state plasma concentrations are attained
of subjects preferred the 3 times/week treatment.
within 5 days of once-daily dosing, and exposure is
However, differences in study design, duration of
approximately 1.6-fold greater than after a single
treatment, dosing regimens, study population
demography, eligibility criteria, study outcome
In the first randomised placebo controlled trial of
measures and methods of data analysis make
daily dosing of tadalafil, Porst et al. report that
comparison between studies difficult. Furthermore,
once-daily dosing of tadalafil 5 and 10 mg signifi-
preference studies have inherent methodologic
cantly improved all erectile function primary and
flaws, resulting in poor internal validity attributable
secondary outcome measures, compared with pla-
to study design biases and confounding errors, thus
cebo ( p < 0.001), and was well tolerated. Successful
making generalization of their results to men
completion of intercourse was reported in 72.8% of
seeking treatment for ED difficult or impossible.
attempts with tadalafil 10 mg, compared with 36.7%
Whilst chronic dosing of tadalafil may have a
with placebo. Furthermore, the EF domain score was
potential role as a treatment for ED, its utility is
increased into the normal range (26) in 50.5% of
limited by current high cost and the reality that the
subjects treated with tadalafil 10 mg. Of particular
average 5–6 times per month intercourse require-
interest is the report that changes from baseline to
ments of the typical ED patient are met adequately
end point were similar for both doses of tadalafil,
by on-demand tadalafil. Tablet splitting, although
suggesting 5 mg as the optimal starting dose. The
not recommended by the manufacturer, is common
frequency of treatment emergent adverse events
in daily office practice and may reduce the cost of
was similar to that reported in an earlier integrated
chronic dosing to a level acceptable to many
analysis of 11 on-demand tadalafil trials and
patients. A potential role exists for chronic dosing
included dyspepsia, headache, dyspepsia, back pain
of tadalafil, alone or in combination with on-
and myalgia. These adverse effects were mild to
demand tadalafil or intracavernous injection ther-
moderate in severity in 86.6% of subjects, prompted
apy, in the salvage of on-demand PDE-5 failure in
discontinuation of the study in 3.4% of subjects and
patients with severe and challenging ED such as
reflect the pharmacologic action of tadalafil as a
diabetic ED, severe vasculogenic ED, post-radical
prostatectomy ED or comorbid hypertension. Of
Efficacy, tolerability and preference for chronic
particular interest is the putative place of chronic
dosing of tadalafil have been reported previously by
dosing of tadalafil for ED prophylaxis in men
other authors using once-daily or alternate
following a nerve-sparing radical retropubic pros-
day dosing regimens in uncontrolled, open-label
tatectomy (NSRRP) in which intraoperative neur-
design studies. Daily dosing of tadalafil (10–20 mg)
apraxia may delay recovery of cavernous nerve
was reported as an effective salvage therapy for
function and return of potency for up to 2 years. It is
patients unresponsive to on-demand tadalafil
widely accepted that early ED prophylaxis/treat-
In a study population of men with severe, pre-
ment may interrupt the progressive apoptotic loss of
dominantly organic ED and a high incidence of
corporal smooth muscle and the increased deposi-
vascular risk factors who satisfied rigorous criteria
tion of extracellular matrix attributable to chronic,
for on-demand tadalafil treatment failure, daily
corporal, hypoxia-induced, increased production of
dosing of tadalafil significantly enhanced all efficacy
transforming growth factor-b1, which results in the
outcome variables, compared with baseline and on-
eventual development of structurally based corpor-
eal veno-occlusive dysfunction. Levine et al.
In a second study, the efficacy and safety of on-
reported that nightly administration of sildenafil
demand tadalafil 20 mg and daily tadalafil 10 mg
post-NSRRP increased the return of spontaneous
were compared by using a 26-week, open-label,
erections 6-fold, compared with placebo.
parallel arm, crossover study design . The mean
Randomised, open-label, comparator and patient
change from baseline for all erectile function
PDE-5 preference studies have highlighted the
primary and secondary outcome measures was
importance that patients place on the ability to
significantly higher for daily-dosed tadalafil, com-
achieve an erection several hours after dosing, as
e u r o p e a n u r o l o g y 5 0 ( 2 0 0 6 ) 2 1 5 – 2 1 7
seen with long half-life PDE-5 inhibitors such as
[3] Kaiser DR, Billups K, Mason C, Wetterling R, Lundberg JL,
tadalafil, and report higher levels of overall patient
Bank AJ. Impaired brachial artery endothelium-depen-
satisfaction, compared with sildenafil With
dent and -independent vasodilation in men with erectile
regards to the reestablishment of sexual spontane-
dysfunction and no other clinical cardiovascular disease. J
ity as an important treatment attribute, some
[4] Desouza C, Parulkar A, Lumpkin D, Akers D, Fonseca VA.
patients may chose chronic dosing regimens to
Acute and prolonged effects of sildenafil on brachial
almost completely remove the need for planning a
artery flow-mediated dilatation in type 2 diabetes. Dia-
sexual encounter. Furthermore, younger men with
psychogenic ED often report on-demand PDE-5
[5] Kimura M, Higashi Y, Hara K, et al. PDE5 inhibitor silde-
inhibitor failure on those occasions when they
nafil citrate augments endothelium-dependent vasodila-
needed to plan sexual activity; their concern that
tion in smokers. Hypertension 2003;41:1106–10, Epub 2003
on-demand PDE-5 inhibitors may not be effective
exacerbate already present high levels of perfor-
[6] Katz SD, Balidemaj K, Homma S, Wu H, Wang J, Maybaum S.
mance anxiety. Interim tadalafil chronic-dosing
Acute type 5 phosphodiesterase inhibition with sildenafil
regimens alone or in combination with cognitive
enhances flow-mediated vasodilation in patients with
behavioural therapy potentially may offer these
chronic heart failure. J Am Coll Cardiol 2000;36:845–51.
[7] Rosano GMC, Aversa A, Vitale C, Fabbri A, Fini M, Spera G.
patients a higher level of efficacy assurance and
Chronic treatment with tadalafil improves endothelial
improved treatment outcomes, and may improve
function in men with increased cardiovascular risk. Eur
the potential for restoration of potency.
In conclusion, treatment of ED with daily tadalafil
[8] Caretta N, Palego P, Ferlin A, et al. Resumption of sponta-
appears effective, safe and well tolerated. Chronic
neous erections in selected patients affected by erectile
dosing regimens of tadalafil may have a role in the
dysfunction and various degrees of carotid wall altera-
routine management of selected patients with ED, in
tion: role of tadalafil. Eur Urol 2005;48:326–31.
the management of treatment refractory ED or as
[9] Behr-Roussel D, Gorny D, Mevel K, et al. Chronic sildenafil
post-NSRRP ED prophylaxis. It may be associated
enhances erectile responses and endothelium-dependent
with higher levels of patient and partner sexual, and
corporal relaxations of normal rats: lack of tachyphylaxis.
overall satisfaction and consequential improve-
ments in the quality of relationships. Further
[10] Jackson G. Hemodynamic and exercise effects of phos-
phodiesterase 5 inhibitors. Am J Cardiol 2005;96:32M–6M.
controlled efficacy, tolerability and patient prefer-
[11] Porst H, Giuliano F, Glina S, et al. Evaluation of the efficacy
ence studies are required to determine the optimal
and safety of once-a-day dosing of tadalafil 5 mg and
dose, the frequency of chronic dosing, the time
10 mg in the treatment of erectile dysfunction: results
course for improvement in erectile function, the
of a multicenter, randomized, double-blind, placebo-
potential for the development of drug tolerance and
controlled trial. Eur Urol 2006;50:351–9.
the full spectrum of patient and partner psycholo-
[12] McMahon CG. Efficacy and safety of daily tadalafil in men
with erectile dysfunction previously unresponsive to on-demand tadalafil. J Sex Med 2004;1:292–300.
[13] McMahon CG. Comparison of efficacy, safety, and toler-
ability of on-demand tadalafil and daily dosed tadalafil for
Dr McMahon is an investigator, member of an advi-
the treatment of erectile dysfunction. J Sex Med 2005;2:415–25.
sory board and/or speaker’s panel for Johnson &
[14] Mirone V, Costa P, Damber JE, et al. An evaluation of an
Johnson, Janssen-Cilag, Ortho McNeil, Pfizer, Icos-
alternative dosing regimen with tadalafil, 3 times/week,
for men with erectile dysfunction: SURE study in 14European countries. Eur Urol 2005;47:846–54.
[15] Levine LA, McCullough AR, Padma-Nathan H. Longitudi-
nal randomized placebo-controlled study of the return ofnocturnal erections after nerve-sparing radical prosta-
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[16] Eardley I, Mirone V, Montorsi F, et al. An open-label,
[2] Saenz de Tejada I, Goldstein I, Azadzoi K, Krane RJ, Cohen
multicentre, randomized, crossover study comparing
RA. Impaired neurogenic and endothelium-mediated
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relaxation of penile smooth muscle from diabetic men
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with impotence. N Engl J Med 1989;320:1025–30.